Vaginal progesterone tablet

ABSTRACT

A vaginal progesterone suppository is provided in the form of a tablet which delivers biologically effective amounts of progesterone for at least about 48 hours, and blood amounts above basal levels for 72 hours. The tablet is formulated to preferably have a hardness on its edge of 8-13 kg, and disintegrates from its surface to form a milky suspension in 6-8 hours after it is inserted in the vaginal vault. The tablet contains, by weight, about 13-20% progesterone, 65-85% lactose, 2-10% corn starch paste binder, 3-10% corn starch disintegrant, and 0.1-0.9% magnesium stearate as a lubricant. The ratio by weight of progesterone to lactose is preferably 1:6, and the ratio of starch paste binder to starch disintegrant is preferably 1:1. This dosage form is an effective treatment for many progesterone deficiency conditions, and provides enhanced bioavailability.

This is a division of application Ser. No. 238,535, filed Aug. 30, 1988.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to vaginal suppositories and methods ofintra-vaginal delivery of drugs. More particularly, it concernstreatment of progesterone deficiency conditions with a vaginal tablet orinsert. 2. General Discussion of the Background

The major biologic functions of progesterone are to prepare the uterineendometrium for fertilization and implantation and to support pregnancy.In addition, progesterone has the ability to inhibit the rhythmiccontractions attributed to the natural spontaneous contractileproperties of the myometrial layer of the uterus.

The secretion of progesterone by the ovary begins just prior toovulation from the follicle that is destined to release an ovum. Afterovulation, the follicle becomes the corpus luteum, which is the primarysource of endogenous progesterone. Progesterone converts estrogen primedproliferating endometrial cells of the uterus into mature secretorycells. During this conversion, mature endometrial cells and glands areproduced, along with blood vessels and carbohydrates necessary tosupport a fertilized ovum if conception occurs. If conception does notoccur, the corpus luteum regresses and progesterone productiondecreases. This leads to necrosis of the endometrial cells and glandswith sloughing of the epithelial layer of the endometrium.

During normal formation of the uterine endometrium within a menstrualcycle, estrogens are necessary for cellular proliferation andprogesterone is needed for maturation and secretory gland formation. Anestrogen stimulated proliferative endometrium must be present forprogesterone to induce a secretory endometrium. If an estrogen primedproliferative endometrium does not proceed to a secretory phase, itusually is because of anovulation and insufficient progesteroneproduction. If insufficient progesterone exists, then minimal to nosecretory epithelium is formed and menstrual bleeding is incomplete ordoes not occur.

The natural secretion of progesterone is 1-2 mg/day during thefollicular phase of the menstrual cycle. During the luteal phase, therate of secretion increases to 10-20 mg/day. The reference serum levelsfor progesterone are 0.1-1.5 ng/ml for the follicular phase and 2.5-28.1ng/ml for the luteal phase. For mid-luteal phase, values of 5.7-28.1ng/ml are reported. In the later stages of pregnancy, the secretion isseveral hundred mg/day of progesterone.

Inactivation of progesterone takes place largely in the liver. Whilemost of the metabolites of progesterone are unidentified, one of themajor urinary products is the glucuronide of pregnane-3a,20a-diol. About50 to 60% of administered radiolabeled progesterone appears in the urineand about 10% in feces. Pregnanediol in urine accounts for 12 to 15% ofthe progesterone metabolized.

The rate of turnover of endogenous progesterone is rapid, the plasmahalf-life being a few minutes. The half-life of progesterone afterintravenous injections has two phases. The first half-life is 5-6minutes and the second is 42-45 minutes. A small amount of progesteroneis stored in body fat, but this is generally regarded as quantitativelyunimportant.

In the absence of organic pathology, such as submucous fibroids, uterinecancer, or infections, the infrequency or absence of the menstrual bleedusually results from abnormalities in the production of estrogen and/orprogesterone. Such conditions are usually referred to as amenorrhea orfunctional uterine bleeding. It is usually impossible to reduce theissue of the etiology of abnormal menstrual function, to a single factorexcept in disease states such as pituitary tumors. The following canalter the production of progesterone and result in progesteronedeficiency conditions:

1. Ovarian Failure. Hypergonadotrophic hypogonadism, or the inability ofthe ovary to respond to any gonadotrophic stimulation, is usually due tothe absence of follicular tissue on a genetic basis.

2. Central Failure. Hypogonadotrophic hypogonadism, involveshypothalamic or pituitary suppression expressed in low serumgonadotrophins.

3. Anovulatory Dysfunction. The- patient who has asynchronousgonadotrophin and estrogen productions and does not ovulate can presentwith a variety of clinical manifestations. The associated clinical signsand symptoms depend upon the level of gonadal function preserved. Lackof or infrequent menstrual bleeds is a common finding.

By definition, amenorrhea is the failure to menstruate. It is a symptomrather than a disease and has many possible causes. Amenorrhea canresult from disturbed reactions anywhere in thehypothalamic-pituitary-ovarian-uterine axis, with or without anassociated organic lesion. Any patient who has a history of previouslymenstruating, but who now has absence of menstrual bleeding with anegative pregnancy test, is usually evaluated for the clinical problemof amenorrhea.

The normal ovulatory function of the menstrual system relies on adynamic coordination of complex actions. Thus, a minor deficiency in theestradiol signal may be associated with a subnormal central response andan impaired or inappropriate degree of follicular growth and function.Dysfunction is sustained by abnormal fluctuations in the internalfeedback mechanisms within the hypothalamic - pituitary - ovariansystems, and functional uterine bleeding may become a persistentproblem. This usually results in erratic menstrual bleeding patterns.

Thus, failure to menstruate or infrequent or incomplete menstrualbleeding, in the absence of pathology, is usually associated withinsufficient quantities of estrogens to initiate the proliferative phaseof the endometrium and/or the absence of progesterone to convertestrogen-primed endometrium into a mature decidual epithelium withsecretory glands and cells. The latter transformation to a matureepithelium must occur prior to any type of sloughing. The sloughing andconcomitant bleeding is recognized as menstruation. Absence ofendometrial maturation under the influence of progesterone results inamenorrhea.

The commonly employed routes of progesterone administration havelimitations (Steege et al., Fertil. Steril. 46:727-729 (1986)).Absorption of orally administered micronized progesterone is influencedby stomach contents, first-pass liver metabolism and other unknownfactors, resulting in significant but highly variable serum levels, thusreducing the therapeutic usefulness of oral progesterone. These problemswith oral administration are sometimes avoided by using syntheticprogestins. The absorption of progesterone by the rectal route isinfluenced by the first-pass effects of the liver and absorption ishighly variable, thus limiting that pathway of administration.Parenteral administration requires deep intramuscular injections whichare often very painful and irritating at the site of injection. Althoughparenteral administration permits the use of natural hormones ratherthan progestins, variations in peak plasma levels require dosages of 5to 10 mg daily for 6 to 8 days.

Since progesterone is absorbed via the vaginal epithelium and it is notcommercially available as a vaginal preparation, pharmacists routinelycompound fatty acid and cocoa butter progesterone suppositories forpatient use. Unfortunately, these suppositories are expelled from thevagina by coughing or sneezing. Moreover, the suppository quickly melts,which allows it to leak out of the vagina and soil a patient's clothing.The rapid dissolution of these prior vaginal suppositories has alsogreatly reduced.. their bioavailability.

A contraceptive vaginal tablet is disclosed in U.S. Pat. No. 4,565,694.It contains boric acid, tartaric acid, vitamin K₃, a lubricant andsufficient disintegrants to disintegrate quickly after vaginalinsertion. Quick dissolution of the tablet allows dispersal of itsspermicidal contents, but greatly reduces the bioavailability of anydrug contained in the tablet.

U.S. Pat. No. 4,585,782 discloses a vaginal tablet for rapidlydispersing an antimycotic composition. The composition is formulated toreduce the pH of the formulation to about 3-6. This low pH greatlyincreases the rate of release of the entire composition. Unfortunately,sustained release of a drug is not possible with such a tablet.Bioavailability of the drug is therefore reduced.

It is therefore an object of this invention to provide a vaginal tablethaving prolonged bioavailability.

It is another object of this invention to provide such a tablet which issuitable for treating progesterone deficiency conditions.

Yet another object of the invention is to provide a vaginal suppositoryin which the pharmaceutically active component is retained within thevagina.

SUMMARY OF THE INVENTION

These and other objects of the invention are achieved by a vaginaltablet which contains progesterone and a carbohydrate in sufficientamounts to deliver biologically effective amounts of progesterone for atleast about 48 hours, and preferably 72 hours, after the tablet isinserted into a human vagina. The tablet is formulated to have ahardness on its edge in the 8 to 13 kg range, most preferably 9-10 kg,such that the tablet disintegrates from its surface after insertion intothe low moisture environment of the vagina. Within about 6-8 hours, thetablet disintegrates completely and forms a micronized, milky suspensionwhich dissolves in the vaginal fluids. The micronized tablet is retainedin the vaginal fluids and absorbed through the vaginal epithelium for aprolonged period of time.

The tablet contains a therapeutic amount of progesterone, an excipient,and a disintegrant. The excipient is preferably lactose, while thedisintegrant is preferably a carbohydrate, preferably starch, especiallycorn starch. It is also desirable to add a lubricant, such as magnesiumstearate, in amounts less than 1% by weight.

The vaginal tablet contains about 13-20% progesterone, 65-85% lactose,2-10% starch paste, 3-10% corn starch, and 0.1-0.9% magnesium stearate,preferably 12-14% progesterone, 78-81% lactose, 2-4% starch paste, 2-4%corn starch, and 0.4-0.6% magnesium stearate, and most preferably 13.5%progesterone, 79% lactose, 3.5% starch paste, 3.5% corn starch, and .52%magnesium stearate.

In preferred embodiments, the tablet includes about 7% starch by weight,most preferably about 13.5% starch by weight as a binder and about 3.5%starch by weight as a disintegrant. The lactose and progesterone arecontained in a granule, and the disintegrant surrounds the granule. Alubricant, such as magnesium stearate, is also included in the tablet.

In especially preferred embodiments, the vaginal tablet includes, byweight, about 13.5% progesterone, 79% lactose, 7% corn starch (3.5% as abinder and 3.5% as a disintegrant), and 0.5% lubricant such as magnesiumstearate. The progesterone is micronized such that the majority of theparticles, preferably at least 80%, are less than about a micron indiameter. The lactose and starch particles should be less than about 50microns in diameter. These fine particle sizes provide comfort to thepatient, and increase the surface area of the drug such that it goesinto solution quickly. The small particle sizes pass more easily throughthe vaginal epithelium than do larger particles.

The ratio of progesterone to lactose is preferably about 1:6 to provideoptimum disintegration with sustained bioavailability of theprogesterone. The ratio of binder to disintegrant is also preferablyabout 1:1. Optimum disintegration of the tablet in the vagina is usuallyobtained if a tablet disintegrates in 4-6 minutes using thedisintegration test (701) described in USP XXI.

The invention also includes a method of making a vaginal tablet byforming a wet granulation of a therapeutic amount of progesterone, afiller excipient, and a binding agent for binding the progesterone andexcipient. The granulation is then dried to form dry granules, which arethen blended with a disintegrant in sufficient amounts to form a tabletwhich delivers biologically effective amounts of progesterone for atleast about 48 hours, and preferably about 72 hours, after the tablet isinserted into a human vagina. In preferred embodiments, the dry granulesand disintegrant are also blended with a lubricant and compressed into adiamond shaped tablet which is retained within the vagina. In especiallypreferred embodiments, the diamond shaped tablet is 2.5 cm long, 1.3 cmwide, and 0.5 cm thick for maximum retention.

The vaginal tablet is suitable for treating a variety of progesteronedeficiency conditions such as menstrual irregularities (amenorrhea),functional uterine bleeding, luteral phase defects, premenstrualtension, in osteoporosis therapy, infertility, ovarian failure,hypogonadotrophic hypogonadism, and anovulatory dysfunction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a top perspective view of a vaginal tablet made in accordancewith the present invention.

FIG. 2 is a top view of the tablet of FIG. 1.

FIG. 3 is a cross sectional view of the tablet taken along lines 3--3 ofFIG. 1.

FIG. 4 is a graph showing mean bioavailability of progesterone from asingle 200 mg progesterone vaginal tablet made in accordance with thepresent invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention is a solid dosage form of progesterone thatdisintegrates by a surface erosion mechanism. This dosage form wasdeveloped for intravaginal use to treat gynecological problemscharacterized by progesterone deficiency, such as amenorrhea, functionaluterine bleeding, luteal phase defects, premenstrual tension, andinfertility, as well as in osteoporosis therapy. It has been found thatthese conditions respond much better to prolonged administration than tothe quick release vaginal tablets of the prior art which delivered drugsother than progesterone.

The tablet is preferably formulated to erode in the vagina during a 6 to8 hour period. The eroding tablet produces micronized particles of thedrug which are dispersed in the vagina as a milky suspension along withthe other ingredients in the tablet. These micronized particles areretained in vaginal fluids for about 48-72 hours, during which timesustained bioavailability of progesterone is attained. Production of themicronized particles of the milky suspension requires careful selectionof the filler excipient. Typical excipients such as microcrystallinecellulose, calcium sulfate, and directly compressible sugars such assucrose, dextrose and fast-flolactose are unsuitable for producing thefine, milky suspension of progesterone. These unsuitable excipientsproduce a gritty suspension that is uncomfortable to the patient andresults in reduced bioavailability of progesterone.

The optimization of disintegration times for vaginal tablets is quitedifferent from more traditional theoretical and practical approachesthat are utilized for oral dosage forms. The tablet excipients, forexample, employed in oral dosage forms cannot be included in the vaginaldelivery system of the present invention. The differing amounts ofmoisture present in the mouth and vagina are primarily responsible forthe different approaches required in these two regions. Although largeamounts of "super disintegrants" can explode tablets very quickly inmoist environments such as the mouth, the present inventors havedetermined that super disintegrants in a vaginal tablet turn the tabletinto a sponge-like mass following vaginal insertion. A milky suspensionis not formed, and drug absorption is retarded. Smaller amounts of thesuper disintegrants cause a gelatinous sheath to form around the tablet,which inhibits further tablet disintegration and thereby reduces drugbioavailability. The present invention avoids these problems by using astarch disintegrant, particularly corn starch, instead of the superdisintegrants of the prior art. Examples of such unsuitable prior artsuper disintegrants are cross-linked polyvinylpyrrolidone, sodium starchglycolate, or croscarmellose at the 2-4% level.

In addition to the choice of disintegrant, the selection of the binderor adhesive is extremely important. Corn starch paste was found to bethe superior binding agent in the present invention, followed bypolyvinyls. These agents were found to be superior to more traditionalbinding agents such as acacia, gelatin, sodium alginate and other gumlike agents. The binder allows the progesterone and lactose to bind toone another, which renders the progesterone more hydrophilic and capableof moving through the vaginal epithelium.

Other starches besides corn starch can be used as the disintegrant orbinder. Examples of such other starches are rice starch, wheat starch,and potato starch.

The optimum formulation and methods of manufacture and use of the tabletare disclosed in the following examples.

EXAMPLE 1

The optimum tablet formulation containing 200 mg of progesterone is, byweight:

    ______________________________________                                        Progesterone, USP    13.50%                                                   Lactose, USP (filler excipient)                                                                    79.00%                                                   Corn starch paste (binder)                                                                          3.49% (dry weight)                                      Corn starch (disintegrant)                                                                          3.49%                                                   Magnesium stearate, USP (lubricant)                                                                 0.52%                                                   ______________________________________                                    

The progesterone USP was a micronized powder obtained from the UpjohnCompany. More than 50% of the micronized particles had diameters lessthan about one micron. Preferably about 80% of the particles should havediameters less than a micron. The physical and chemical characteristicsof the progesterone were:

1. Chemical Name: Progesterone; pregn-4-ene-3,20-dione;4-pregnene-3,20-dione

2. International Nonproprietary Name: Progesterone

3. Empirical Formula: C₂₁ H₃₀ O₂

4. Structural Formula: ##STR1##

The lactose was obtained in a powdered form from Sheffield Productsunder the product name Lactose Hydrous USP. The diameters of the lactoseparticles in the powder were less than about 50 microns.

The corn starch was obtained in a powdered form from Staley Mfg. Co.under the product name Corn Starch USP. The diameters of the starchparticles in the powder were less than about 50 microns.

Magnesium stearate was obtained from Mallinckrodt, Inc. under theproduct name Magnesium Stearate USP.

EXAMPLE 2

The tablet of Example 1 was manufactured in the following manner.

The lactose and the progesterone were mixed in a V-blender for 15minutes and then transferred to a Hobart mixer. The starch paste wasadded to the lactose:progesterone blend to prepare the granulation. Thestarch paste was at an 18% w/v percentage in the optimized product. Thedamp mass was then passed through a number 12 screen and the granuleswere dried for three hours at 50° C. The moisture content at this stagewas less than 1%. The granules were then passed through a 20 mesh screenand weighted. The corn starch which had previously been screened througha 60 mesh screen was blended in with the dry granules for five minutesand the pre-screened magnesium stearate was then added to the granulesand blended for an additional four minutes. The corn starch powder andthe magnesium stearate were adjusted on the basis of the percent yieldof dry granules and the moisture content, to ensure that the percent ofingredients in the finished dosage form was the same as the percentageslisted in the above formula. The dry granules were then compressed intohard pressed, diamond shaped white tablets with bevelled edges, as shownin FIGS. 1-3. The tablet was 2.5 cm long, 1.3 cm at its maximum width,and 0.5 cm thick. The edges on both flat surfaces were bevelled at 45°angles, with 0.1 cm reduction in height, width and length on all edges.

The tablet hardness for a diamond.. shaped tablet on its edge was in the8 to 13 kg range, with 9 to 10 being the most desirable. Tablets thatexceeded the 13 kg hardness level gave a slower disintegration time invivo, which reduced progesterone blood levels in vivo.

Tablet hardness was determined by a Haberlein hardness tester. Thetablet is placed flat on a surface and compressed between a pair ofplates which measure the maximum compression force on the tablet when itdisintegrates.

Tablet disintegration time in water was 4-6 minutes using USP XXIPhysical Test (701) for disintegration of an uncoated tablet.Disintegration time in the vagina was 6-8 hours.

EXAMPLE 3

Although optimum results are obtained with the formulation of Example 1,other vaginal tablets were prepared and tested having ingredients in thefollowing ranges:

    ______________________________________                                        Progesterone, USP 13-20%                                                      Lactose, USP      65-85%                                                      Starch paste       2-10%    (dry weight)                                      Corn starch        3-10%                                                      Magnesium stearate, USP                                                                         0.10-0.9%                                                   ______________________________________                                    

Specific formulations are given in the following Examples 4-6 in whichthe corn starch paste was prepared by mixing the corn starch with 40 mlof water. The progesterone and paste were then wet granulated and driedin open air overnight. The granulation was then combined with the cornstarch disintegrant and powdered lactose, then mixed in a blender for 10minutes. The magnesium stearate was added, and the granulation was thenmixed an additional 4 minutes. The tablet hardness range for each ofExamples 4-6 was 10-12 kg. Each of the tablets disintegrated in lessthan 43 seconds in a beaker using the USP XXI (Physical Test 701)disintegration test for uncoated tablets.

EXAMPLE 4

    ______________________________________                                                            g/tablet                                                  ______________________________________                                        Progesterone      15.38%  0.199                                               Lactose Q.S.      76.02%  0.989                                               Starch paste      4%      0.052                                               Corn starch       4%      0.052                                               Magnesium stearate                                                                              0.6%    0.0078                                              Tablet weight             1.3                                                 ______________________________________                                    

EXAMPLE 5

    ______________________________________                                                            g/tablet                                                  ______________________________________                                        Progesterone     14.28%   0.199                                               Lactose Q.S.     77.8%    1.0894                                              Starch paste     3.71%    0.0519                                              Corn starch      3.71%    0.0519                                              Magnesium stearate                                                                             0.56%    0.0078                                              Tablet weight             1.4                                                 ______________________________________                                    

EXAMPLE 6

    ______________________________________                                                            g/tablet                                                  ______________________________________                                        Progesterone     13.33%   0.199                                               Lactose Q.S.     79.21%   1.19                                                Starch paste     3.47%    0.052                                               Corn starch      3.47%    0.052                                               Magnesium stearate                                                                             0.52%    0.0078                                              Tablet weight             1.5                                                 ______________________________________                                    

EXAMPLE 7

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        Progesterone      15.38%   200                                                Corn starch (binder)                                                                            3.0%     39                                                 Corn starch (disintegrant)                                                                      6.0%     78                                                 Magnesium stearate                                                                              0.5%     6.5                                                Na CMC            0.01%    0.13                                               PVP K 29-32       0.01%    0.13                                               Lactose           75.38%   979.9                                              Aerosol OT        0.05%    0.65                                               Tablet weight              1.3 g                                              ______________________________________                                    

The progesterone and lactose were blended and mixed for 15 minutes. Thebinder paste was then prepared by mixing 9 g corn starch with 61 ml ofwater containing 0.15 g aerosol OT to give a total weight of 70.15 g.From this binder mixture, 63 g was used, or 2.7% corn starch and 0.043%aerosol OT. The blended progesterone, lactose and binder paste formed awet granulation which was passed through a #12 sieve and then put in anoven for 3 hours at 50° C. to produce a dry granulation. The drygranulation was passed through a #20 sieve, corn starch was added, andthe mixture blended for 10 minutes. The sodium carboxymethylcelluloseand polyvinylpyrrolidone were added to the mixture and blended for 5minutes.

The resulting tablet weight was about 1.3g. Maximum tablet hardness was6 to 8 kg. The tablet disintegrated in water in 25-31 seconds, which wasfaster than desired.

EXAMPLE 8

    ______________________________________                                        Progesterone            20%                                                   Fast flow lactose       71.5%                                                 Corn starch (binder)    1.5%                                                  Corn starch (disintegrant)                                                                            6.0%                                                  Magnesium stearate      1.0%                                                  ______________________________________                                    

The corn starch binder paste was prepared by mixing 1.5g corn starchwith 18 ml of water. The progesterone binder paste were wet granulated,then passed through a #12 sieve and placed in an oven for 3 hours at 50°C. The dried granulation was passed through a #20 sieve, and the fastflow lactose (which was obtained from Foremost Whey Products underproduct designation Fast Flo Lactose) was added. The mixture was blendedfor 15 minutes, the corn starch added, and then blending was continuedfor 5 more minutes. The magnesium stearate was added, the mixtureblended for 5 more minutes, and then tablets were formed by compression.

The tablet weight was 482-490 mg, hardness was 8-9 kg, anddisintegration time was 333-369 seconds. This disintegration time waswithin desirable ranges of 300-360 seconds. The fast flow lactose,however, produced gritty particles that were uncomfortable to thepatient.

EXAMPLE 9

The same procedure was used as in Example 8, except 1.5% magnesiumstearate was used instead of 1%, and 71% fast flow lactose was usedinstead of 71.5%. The resulting formulation was:

    ______________________________________                                        Progesterone            20%                                                   Fast flow lactose       71%                                                   Corn starch (binder)    1.5%                                                  Corn starch (disintegrant)                                                                            6.0%                                                  Magnesium stearate      1.5%                                                  ______________________________________                                    

The tablet weight was 490.2-500.7g, hardness was 8.5-10.0 kg, anddisintegration time in water was 250-265 seconds. Once again, however,the large particle sizes of the fast flow lactose produced a grittysuspension in the vagina that was uncomfortable to patients.

EXAMPLE 10

    ______________________________________                                        Progesterone        20%                                                       Lactose             70%                                                       Corn starch (binder)                                                                              3%                                                        Corn starch (disintegrant)                                                                        6%                                                        Magnesium stearate  1%                                                        ______________________________________                                    

Tablet weight was 1.0075-1.0139g, and tablet hardness was 4.75-5.25.Disintegration time was 21-23 seconds, which was consistent with therelatively low tablet hardness. The disintegration time was much fasterthan the preferred 300-360 seconds.

EXAMPLE 11

    ______________________________________                                        Progesterone        15.38%                                                    Corn starch (binder)                                                                              3.0%                                                      Corn starch (disintegrant)                                                                        5.0%                                                      Magnesium stearate  0.8%                                                      Lactose Q.S.        75.82%                                                    ______________________________________                                    

Tablet weight was 1.33-1.41g. Tablet hardness was 10.5-11.25 kg, anddisintegration time in water was 52-60 seconds.

EXAMPLE 12

    ______________________________________                                        Progesterone            20%                                                   Fast flow lactose       71%                                                   Corn starch (binder)    1.5%                                                  Magnesium stearate      1.5%                                                  Corn starch (disintegrant)                                                                            6.0%                                                  ______________________________________                                    

Tablet hardness was estimated to be 8-10 kg.

EXAMPLE 13

    ______________________________________                                        Progesterone            20%                                                   Corn starch (binder)    1.5%                                                  Fast flow lactose       71.5%                                                 Corn starch (disintegrant)                                                                            6.0%                                                  Magnesium stearate      1.0%                                                  ______________________________________                                    

Tablet hardness was estimated to be 8-10 kg.

EXAMPLE 14

The tablet of Example 1 was also prepared by a recompression techniquewithout the use of aqueous media. Progesterone, lactose and the cornstarch in the powder form were combined with half the magnesium stearateand blended prior to making large brittle compacts (tablets). Thesecompacts were then broken into smaller granules, combined with theremaining lubricant (magnesium stearate), and then compressed during anormal tableting procedure to make the finished dosage form. Thecontents of the recompressed and the single compressed tablets areessentially the same.

The tablet prepared by recompression techniques without the use ofaqueous media was inferior to the tablets prepared by the method ofExample 2. The recompressed tablet rapidly decomposed after insertion inthe human vagina, instead of slowly disintegrating from its surface for6-8 hours. The tablet itself was friable and brittle, and did notproduce the microcrystalline dispersion described earlier for maximumbioavailability. Tablet hardness was 8-10 kg and disintegration timeusing USP XXI was 60-90 seconds.

EXAMPLE 15

All disintegration times were determined using the USP XXIdisintegration procedure (Physical Test 701) and 500 ml of buffer pH 7.4at 37° C. In the preferred embodiments of the composition, completedisintegration occurred in the 1-6 minute range, most preferably 5-6minute range, using the USP XXI disintegration test procedure. This timeperiod appears to be quite rapid compared to the 6-8 hour preferreddisintegration time in the human vagina. The small amount of biologicalfluid in the vaginal area, however, greatly prolongs the disintegrationtime in vivo. Significant differences in body absorption of progesteroneoccur between the present product and tablets or suppositories thatwould disintegrate in less than a minute, or even less than 4-6 minutes.

Tablets or suppositories that disintegrate in less than a minute invitro swell rapidly in vivo, removing the surrounding fluid in thevaginal tract and decreasing the release of drug from the dosage form.The product of the present invention disintegrates by a surface erosionmechanism which is ideal for the site of administration and maximizesthe efficacy and bioavailability of the progesterone.

EXAMPLE 16

The objective of this example was to clinically evaluate the safety andefficacy of a progesterone-200 mg vaginal tablet to produce a withdrawalbleed in patients with amenorrhea and functional uterine bleeding usinga single daily dose of the tablet for seven consecutive days.

A total of twenty-five patients with a history of amenorrhea orfunctional uterine bleeding were treated with 200 mg progesteronevaginal tablets. The tablet was administered by placing it high in thevaginal vault with a vaginal applicator.

Thirteen patients (ages 20-37 years) with a history of amenorrhea andtwelve patients (ages 23-44 years) with a history of functional uterinebleeding were involved in the study. All patients were evaluated for anobjective response using a protocol that required a single 200 mgprogesterone tablet to be inserted vaginally once daily for sevenconsecutive days. All patients were monitored for bioavailability ofserum progesterone during the seven days of treatment. A closesurveillance for toxicities was also made during the treatment and fortwenty-eight days post-initiating therapy. One patient used only fourtablets over a seven day period. The other twenty-four out oftwenty-five patients correctly used seven tablets over seven days. Theoverall response from the progesterone was that twenty-five out oftwenty-five had a complete withdrawal bleed response.

In evaluating responses from start of therapy (Day 1) the following wasobserved:

Thirteen patients with amenorrhea and twelve patients with functionaluterine bleeding demonstrated withdrawal bleeding within one to eightdays after the last progesterone tablet was inserted. One patient withamenorrhea and two patients with functional uterine bleeding had vaginalspotting while on therapy. A second bleed or menstrual cycle occurredtwenty-four days (median) after the last tablet was inserted intwenty-two of twenty-five patients.

All patients absorbed progesterone,-as indicated by the elevation oftheir serum levels above baseline. The mean C_(max) was 12.25 ng/ml witha range of 6.9-20.6 ng/ml. The mean t_(max) was 23.3 hours with a rangeof eight to thirty-six hours. Blood levels remained above the baselinevalue for 72 hours after insertion in four of the six patients. The meanarea under the curve (AUC) was 350.2±52.8 ng hr/ml, with a range of265.6-416.8 ng hr/ml. All patients experienced a withdrawal bleed fourto seven days after the tablet was inserted (Mean=4.7 days).

All patients were carefully evaluated for toxicities. Extensive physicalexaminations and blood studies were performed during the study. Notoxicities, adverse reactions or unexplained laboratory studies wereobserved.

Seven out of twenty-five patients had pre-therapy endometrial biopsiesperformed. Two patients had both pre- and post-therapy biopsies. Allpre-therapy biopsies showed proliferative endometrium. One of thepost-therapy biopsies showed a secretory endometrium. The other remainedin a proliferative phase, but did experience a withdrawal bleeding afterprogesterone therapy. Several patients had minimal or no evidence ofendogenous estrogen priming (vaginal cytology examinations) and, asexpected, had poor absorption of progesterone as indicated by theirplasma progesterone values. However, they all had a withdrawal bleedingpost-therapy.

In summary, thirteen patients with amenorrhea and twelve patients withfunctional uterine bleeding experienced a withdrawal bleed initiated byseven days of therapy with a 200 mg progesterone vaginal tablet.

EXAMPLE 17

The objective of this study was to determine the rate and extent ofabsorption of a single 200 mg progesterone vaginal tablet. A secondaryobjective was to determine the efficacy of a single 200 mg vaginaltablet in producing a withdrawal bleed in patients with amenorrhea andfunctional uterine bleeding.

A total of six female patients (ages 18-30 years) with a history ofamenorrhea, in the absence of organic pathology, were treated with asingle 200 mg progesterone vaginal tablet. All patients had a prestudyserum progesterone level of 2 ng/ml or less.

In this bioavailability study, patients received a single 200 mgprogesterone vaginal tablet at 0 hour and serum progesterone levels weresampled at 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours. Ifthe serum progesterone level had not dropped to 2.0 ng/ml or below after72 hours, additional blood samples were taken every 24 hours until thishad occurred.

Complete physical examinations were performed on visit one and thenseven and twenty-eight days after the tablet was inserted. Theseexaminations included a preliminary history, pelvic examination, and papsmear, as well as temperature, pulse, blood pressure, weight, breastexamination, SMA 20, serum HCG, CBC, PT, PTT, magnesium, lipid profile,and urinalysis at each visit. At visits after the tablet was inserted,the patients were questioned to determine if they had experienced anyvaginal bleeding or spotting, and the dates of such occurrences wererecorded.

The results of the bioavailability study are presented in Table 1 andFIG. 4. All patients absorbed progesterone as indicated by the elevationof their serum levels above baseline. The mean C_(max) was 12.25 ng/mlwith a range of 6.9-20.6 ng/ml. The mean t_(max) was 23.3 hours with arange of eight to thirty-six hours. Blood levels remained above thebaseline value for 72 hours after insertion in four of the six patients.The mean area under the curve (AUC) was 350.2±52.8 ng hr/ml, with arange of 265.6-416.8 ng hr/ml.

                  TABLE 1                                                         ______________________________________                                        BIOAVAILABILITY STUDY                                                         FOR A                                                                         SINGLE 200 MG PROGRESTERONE VAGINAL TABLET                                    Results from Six Patients                                                     (Serum Progesterone Levels - ng/ml)                                           ______________________________________                                        Hour  LG      CW       AF    RP     CC    MF                                  ______________________________________                                        0     0.3     0.9      0.5   0.6    0.6   0.5                                 0.5   1.9     2.3      1.6   1.9    1.2   1.9                                 1     4.5     2.5      2.0   1.6    1.5   3.6                                 1.5   3.6     2.0      1.9   1.7    1.7   5.0                                 2     3.6     2.4      1.6   1.3    1.8   6.2                                 4     1.7     3.3      3.0   4.6    6.4   11.9                                6     2.0     4.3      11.2  13.5   8.3   11.6                                8     2.3     4.7      14.8  16.5   8.3   10.3                                12    3.6     6.5      13.2  20.6   10.7  12.4                                24    4.4     5.6      5.7   8.0    11.3  13.0                                36    6.9     6.9      1.7   2.7    4.7   1.7                                 48    2.3     5.8      1.0   1.4    2.0   0.9                                 72    3.0     0.4      0.8   0.7    1.1   0.2                                 C max 6.9     6.9      14.8  20.6   11.3  13.0                                t max 36 Hr   36 Hr    8 Hr  12 Hr  24 Hr 24 Hr                               AUC   265.6   347.1    299.6 416.8  387.2 385.2                               ______________________________________                                              Mean +/- S.D.  Range      % C.V.                                        ______________________________________                                        C max 12.25 ± 4.742                                                                              6.9-20.6  38.7                                          t max 23.3 Hrs          8-36 Hrs                                                                              --                                            AUC   350.2 +/- 52.82                                                                              265.6-416.8                                                                              15.0                                          ______________________________________                                    

No changes in blood chemistries or other blood values were noted whileon therapy.

No adverse reactions or side effects were reported. All patientsexperienced a withdrawal bleed four to seven days after the tablet wasinserted (Mean=4.7 days).

TABLET DISINTEGRATION PROFILE

Disintegration tests have shown that the vaginal tablet as formulateddisintegrates by a surface erosion mechanism which ideally takes placein vivo during a four to six hour period. The micronized drug is thendispersed in the vaginal region of the body as a milky suspension, whichis then absorbed.

The surface erosion mechanism is an important factor to be consideredbecause it increases the ability of the tablet to remain in the vaginaso that absorption may occur. Studies have shown that fatty acid andglycerine suppositories as they disintegrate, either by melting or bydissolution, are discharged from the vagina. Fulper, L. D., Evaluationof Vaginal Formulations of Progesterone. Masters Thesis. University ofMississippi, 1985. This lowers the bioavailability of the drug.

Because the present tablet disintegrates slowly, the drug is availablein the vagina for a longer period of time and the bioavailability of thedrug is increased. Therefore, as would be expected, elevated serumprogesterone levels were seen 72 hours after tablet insertion resultingin a mean area under the curve (AUC) of 350.2 ng hr/ml (Table 2).

In addition, the slow decline in serum progesterone concentrations shownin the absorption profile in FIG. 4 is also typical of absorptionrate-limited elimination, in which the time course of the drug in thebody is a reflection of its absorption from the dosage form. This typeof absorption rate-limited elimination is expected for a drug with ashort half-life such as progesterone.

The results of the bioavailability study using the presently describedvaginal tablet are compared with results reported by Villanueva et al.[Fertil. Steril. 35:433 (1981)] and Price et al. [Fertil. Steril. 39:490(1983)] in Table 2.

                  TABLE 2                                                         ______________________________________                                        COMPARISON OF AUC OF SERUM PROGESTERONE                                       LEVELS FOR DIFFERENT DOSAGE FORMS                                             Dosage   Progesterone                                                                             AUC            t.sub.max                                                                          C.sub.max                             Force    Dosage     (ng hr/ml)                                                                              Hrs* (hr) (ng/ml)                               ______________________________________                                        Various Dosage Forms (5)                                                      Intramuscular                                                                          50 mg.     184 ± 42                                                                             24   14.4 9.52                                  injection                                                                     Sublingual                                                                             50 mg.     26 ± 7 24   1.3  3.97                                  instillation                                                                  Vaginal  50 mg.      87 ± 21                                                                             24   3.0  7.74                                  suspension                                                                    Vaginal Suppositories (1)                                                     Glycerinated                                                                           25 mg.     14.8 ± 4.7                                                                           24   2.3  2.52                                  gelatin                                                                       Cocoa butter                                                                           25 mg.     25.3 ± 3.1                                                                           24   2.2  6.37                                  PEG      25 mg.     68.3 ± 5.0                                                                           24   3.5  9.72                                  200 mg Progesterone Vaginal Tablet                                            Vaginal  200 mg.    350.2 ±                                                                              72   23.3 12.25                                 Tablet              52.8                                                      ______________________________________                                         *Hours serum progesterone levels remained above baseline.                

The 200 mg progesterone vaginal tablet yielded serum levels ofprogesterone for a longer period of time than the other dosage formsevaluated in the literature. Although the C_(max) value for theprogesterone vaginal tablet was only approximately 3 ng/ml greater thanthat of the injection or PEG dosage, the mean AUC after dosage with asingle 200 mg tablet was twice that for an intramuscular injection andfive times that of the PEG suppository. Because studies using vaginalformulations have not been able to produce elevated serum progesteronelevels for greater than 24 hours, it has been postulated that choice ofbase affects the magnitude of serum progesterone levels, but not thetotal length of time progesterone levels are elevated above baseline[Price et al. (1981)]. In fact, Myers et al. suggested that allexogenous progesterone is metabolized within 24 hours [Fertil. Steril.47:71 (1987)].

The present invention has demonstrated that, contrary to theexpectations of those skilled in this art, blood levels can bemaintained above baseline for an extended period of time merely byaltering the composition of the dosage form.

Having illustrated and described the principles of my invention withreference to one preferred embodiment, it should be apparent to thosepersons skilled in the art that such invention may be modified inarrangement and detail without departing from such principles. I claimas my invention all such modifications as come within the true spiritand scope of the following claims.

We claim:
 1. A method of making a vaginal tablet, comprising the stepsof:forming granules of progesterone and a particulate lactose excipientby mixing powdered progesterone particles with the lactose excipient,and a suitable binding agent for binding the progesterone and excipient;blending the granules with a suitable disintegrant for delivering abovebasal blood levels of progesterone for at least 48 hours after thetablet is inserted into a human vagina; and forming a tablet from theblend of dry granules and disintegrant, the progesterone, lactose,binding agent and disintegrant being provided in sufficient amounts andparticle sizes to deliver progesterone above basal blood levels for atleast 48 hours after the tablet is inserted into a human vagina.
 2. Themethod of claim 1 wherein said blending step comprises blending the drygranules with sufficient amounts of a disintegrant and progesterone todeliver biologically effective amounts of progesterone for at least 72hours after the tablet is inserted into a human vagina.
 3. The method ofclaim 2 further comprising the step of blending the dry granules and thedisintegrant with a lubricant.
 4. The method of claim 1 wherein the stepof forming the tablet comprises compressing the dried granules anddisintegrant into a diamond shaped tablet.
 5. The method of claim 4wherein the tablet forming step comprises forming a tablet having alength of about 2.5 cm., a width of about 1.3 cm., and a thickness ofabout 0.5 cm.
 6. The method of claim 1 wherein the step of forming a wetgranulation comprises mixing the progesterone and lactose in a 1:6ratio.
 7. The method of claim 6 wherein the binding agent anddisintegrant are both corn starch, and the step of blending the drygranules with a disintegrant comprises blending the dry granules withsufficient disintegrant to provide a 1:1 ratio between the binding agentand disintegrant.
 8. The method of claim 3 wherein the step of blendingthe dry granules and disintegrant with a lubricant comprises providingless than 1% by weight magnesium stearate.
 9. The method of claim 7further comprising the step of blending the dry granules and thedisintegrant with less than 1% magnesium stearate.
 10. A method oftreating progesterone deficiency conditions, comprising the stepsof:providing a tablet which comprises an amount of particulateprogesterone sufficient to deliver progesterone above basal bloodlevels, a lactose excipient bound to the progesterone by a suitablebinder, and a disintegrant, the progesterone, lactose, binder anddisintegrant being present in sufficient amounts and particle sizes todeliver above basal blood levels of progesterone for at least 48 hoursafter it is placed in a human vagina; and inserting the tablet in thevagina of a human female having a progesterone deficiency condition. 11.The method of claim 10 wherein the progesterone deficiency conditionincludes amenorrhea as a symptom.
 12. The method of claim 10 wherein theprogesterone deficiency condition includes ovarian failure.
 13. Themethod of claim 10 wherein the progesterone deficiency conditionincludes hypogonadotrophic hypogonadism.
 14. The method of claim 10wherein the progesterone deficiency condition includes anovulatorydysfunction.
 15. The method of claim 10 wherein the progesteronedeficiency condition includes functional uterine bleeding.
 16. Themethod of claim 10 wherein the progesterone deficiency conditionincludes premenstrual tension.
 17. The method of claim 10 wherein theprogesterone deficiency condition includes infertility.
 18. The methodof claim 10 wherein the ratio of progesterone to lactose is 1:6 byweight.
 19. The method of claim 18 wherein the lactose particles areless than fifty microns in diameter.
 20. The method of claim 10 whereinthe progesterone is bound to the hydrophilic excipient by mixing it witha binder selected from the group consisting of corn starch andpolyvinylpyrrolidone.
 21. The method of claim 20 wherein the binder iscorn starch powder.
 22. The method of claim 21 wherein the corn starchpowder particles are less than fifty microns in diameter.
 23. The methodof calim 1 wherein the powdered progesterone contains particles, morethan fifty percent of which are less than one micron in diameter. 24.The method of claim 1 wherein the disintegrant is selected form thegroup consisting of corn starch, rice starch, wheat starch and potatostarch.
 25. A method of making a vaginal tablet, comprising the stepsof:formulating a tablet by mixing an amount of powdered progesteroneparticles with an excipient comprising powdered lactose particles;binding the progesterone to lactose by mixing them with a binderselected from the group consisting of powdered corn starch andpolyvinylpyrrolidone; and forming a tablet by compressing the boundprogesterone and lactose into a tablet with a disintegrant selected fromthe group consisting of corn starch, rice starch, wheat starch andpotato starch, the tablet containing sufficient amounts and particlesizes of progesterone, lactose, binder and disintegrant to deliveramounts of progesterone above basal blood levels for at least 48 hours.26. A method of treating progesterone deficiency conditions comprisingplacing the tablet of claim 25 in the vagina of a woman who has aprogesterone deficiency condition.
 27. The tablet of the method ofclaim
 1. 28. The tablet of the method of claim
 25. 29. The method ofclaim 25 wherein the powdered lactose particles have diameters less thanfifty microns and at least 50% of the progesterone particles havediameters less than one micron.
 30. The method of calim 29 wherein theratio by weight of progesterone to lactose is 1:6.
 31. The method ofclaim 30 wherein the binder is comprised of particles having diametersless than fifty microns.
 32. The method of claim 1 wherein the tabletcontains an amount of progesterone and disintegrant sufficient todeliver amounts of progesterone above basal blood levels for at least 72hours.
 33. The method of claim 32 wherein the hydrophilic fillerexcipient is powdered lactose particles and the binding agent is starch.34. The method of calim 33 wherein the powdered lactose particles areless than fifty microns in diameter and at least 50% of the progesteroneparticles have diameters less than one micron.
 35. The method of claim34 wherein the ratio by weight of progesterone to lactose is 1:6. 36.The method of claim 35 wherein the binder is comprised of particleshaving diameters less than fifty microns.
 37. The method of claim 30wherein the ratio of binder to disintegrant is 1:1.
 38. A method ofmaking a vaginal tablet, comprising the steps of:mixing powderedprogesterone particles with a particulate lactose excipient and abinding agent selected from the group consisting of particulate starchand polyvinyl pyrrolidone such that the binding agent binds the lactoseparticles to the particles of progesterone, wherein the lactose andbinder particles are less than 50 microns in diameter, and at least 50%of the progesterone particles are less than one micron in diameter, theratio of progesterone to lactose is 1:6 by weight, and sufficientprogesterone is present in the tablet to deliver amounts of progesteroneabove basal blood levels; and forming a tablet by compressing the boundprogesterone and lactose with a disintegrant selected from the groupconsisting of corn starch, rice starch, wheat starch and potato starch,wherein the ratio by weight of disintegrant to binder is 1:1.